Proprietary: This proposal includes trade secrets and other proprietary or confidential information of Highland Instruments and is being provided for use by the National Institutes of Health (NIH) for the sole purpose of evaluating this SBIR proposal. No other rights are conferred. This proposal and the trade secrets and other proprietary or confidential information contained herein shal further not be disclosed in whole or in parts, outside of NIH without Highland Instrument's permission. This restriction does not limit the NIH's right to use information contained in the data if it is obtained from another source without restriction. This legend applies to the Abstract, Specific Aims, Research Plan (al components), Commercialization Plan, and Human Subject's Sections of this proposal. Abstract. The USA is undergoing a national crisis of opioid addiction. While opioid therapy is a mainstay approach for the treatment of moderate to severe pain; in the chronic pain (CP) population, 21-29% misuse prescribed opiates, 8-12% develop an opioid related disorder, and 4- 6% transition to heroin [1-3]. Addicts exhibit aberrant brain network states, which may be modified through appropriate therapies to reduce addictive behavior [1, 2]. Recent studies have demonstrated that noninvasive brain stimulation (NIBS) may be effective in treating some forms of addiction [3-10]. However, the most common NIBS methods, e.g., Transcranial Magnetic Stimulation (TMS) and Transcranial Direct Current Stimulation (tDCS), have not been found to be effective in treating opioid use disorder (OUD) ([3, 4]). It has been postulated that limitations in these techniques? focality, penetration, and targeting control limit their therapeutic efficacy [11-15]. Electrosonic Stimulation (ESStim?) is an improved NIBS modality that overcomes these limitations by combining independently controlled electromagnetic and ultrasonic fields to focus and boost stimulation currents via tuned electromechanical coupling in neural tissue [16, 17]. This proposal is focused on evaluating whether our noninvasive ESStim system can effectively reduce OUD in patients prescribed opioids secondary to CP. First in Phase I, to assess the feasibility of the proposed work, we will follow 26 OUD patients after giving a fixed dose of ESStim for 5 consecutive days, 20 min/day (13 Active, 13 SHAM). We will administer a battery of clinical/safety, drug-use, electrophysiology, behavioral, and psychosocial assessments in the OUD patients, evaluated over the treatment period and for at least four weeks following the last treatment session. Next in the Phase II, we will follow 60 OUD patients (30 Active, 30 SHAM) after giving a fixed dose of stimulation for 10 days, 20 min/day. We will evaluate these patients with the same battery of assessments validated in Phase I, but now assessments will be made at least twelve weeks following the last treatment session. In parallel with the OUD treatments, we will build MRI derived models of the stimulation fields in the patients? heads (electric and acoustic field models) to calculate the stimulation field characteristics at the brain target sites. Multivariate linear and generalized linear regression models will then be built and evaluated to predict the patient outcomes as a function of baseline disease characteristics and the MRI based dosing models. The results from the computational work will be used to develop an optimized OUD ESStim treatment dosing model. Overall, we hypothesize that the proposed experiments, computational studies, and technology development will allow us to optimize ESStim? for treatment of OUD secondary to CP and will serve as the foundation to improve the treatment of OUD and addiction in the US.